Incretins and Nutrient induced Plasticity

胰岛素和营养诱导的可塑性肠道不是被动的管道，而是一个巨大的、动态的器官，可以适应营养供应和能量需求的巨大变化。粘膜的结构经历了强大的适应，因为包括上皮细胞增殖、凋亡和分化在内的细胞过程可能会在营养剥夺后下调，并在营养摄入后恢复。由于肠道是一个对能量要求很高的器官，在抵消代谢成本的同时，保持足够的工作能力来吸收营养是至关重要的。肠内分泌L细胞和K细胞分别在餐后迅速分泌胰升糖素样肽1和葡萄糖依赖的胰岛素营养多肽。GLP-1和GIP各自通过不同的G蛋白偶联受体GLP-1R和GIPR发出信号，经典认为它们针对胰岛增加葡萄糖刺激的胰岛素分泌。然而，胰岛素受体在整个胃肠道都有表达，分泌GLP-1和GIP的肠内分泌细胞与肠腔内的营养物质直接接触，微血管和神经系统使它们处于理想的位置，介导从禁食到进食状态的高度适应性反应。本研究旨在发现和定义新的信号通路，通过这些信号通路，生长素激素GIP和GLP-1可以动态调节肠道的结构和功能，以响应营养的摄入。*假设：肠道来源的生长素激素、GLP-1和GIP介导营养诱导的肠道可塑性。*目的：为了明确胰岛素激素在调节营养诱导的可塑性中的作用机制，需要进行大量的关键实验。在野生型(WT)和双内分泌受体敲除小鼠(DIRKO)中，我们将确定：(A)肠道的形态组成是否随喂食而适当改变，(B)细胞的生长和分化，(C)胰岛素信号对消化和养分吸收的影响，(D)肠上皮的凋亡和增殖，(E)在GLP-1R和GIPR缺失的小鼠中，禁食或再喂食所需的关键效应因子的表达水平和蛋白水平是否被阻断。*申请者对本提案中包含的所有技术都有丰富的专业知识；因此，受训者将获得一些补充和复杂的工具/方法，用于分离细胞和适当使用动物，以应用于他们未来的研究计划。*预期结果和相关性：我们期望确定GIPR和GLP-1R信号在调节小肠适应营养摄入方面的关键作用。*

Incretins and Nutrient Induced Plasticity******The intestine is not a passive conduit but a large, dynamic organ which adjusts to large variations in both nutrient supply and energy demand. The structure of the mucosa undergoes robust adaptation as cellular processes including epithelial cell proliferation, apoptosis and differentiation may be downregulated with nutrient deprivation and recovered upon nutrient ingestion. As the gut is an energetically demanding organ, maintaining sufficient work capacity for nutrient absorption while offsetting metabolic cost is vital. Two incretin hormone peptides are secreted from enteroendocrine L cells and K cells respectively, glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) very rapidly post-prandially. GLP-1 and GIP each signal through a distinct G-protein coupled receptor, the GLP-1R and GIPR respectively and are classically thought to target the islet to increase glucose-stimulated insulin secretion. However, the incretin receptors are expressed throughout the gastrointestinal tract and the enteroendocrine cells which secrete GLP-1 and GIP are in direct contact with nutrients in the intestinal lumen, the microvasculature and nervous system making them ideally situated to mediate the highly adaptive response from a fasted to fed state. This proposal aims to identify and define novel signaling pathways through which the incretin hormones GIP and GLP-1 dynamically regulate the structure and function of the intestinal tract in response to ingested nutrients.******Hypothesis: The gut derived incretin hormones, GLP-1 and GIP mediate intestinal nutrient-induced plasticity.***Objectives: In order to define the mechanisms underlying the role of the incretin hormones for mediating nutrient induced plasticity, a number of key experiments are required. In Wildtype (WT) and Double Incretin Receptor Knock Out mice (DIRKO) littermate controls exposed to fasting or post-prandial conditions we will determine if: (a) morphological composition of the gut changes appropriately with feeding, (b) cell growth and differentiation of the epithelium, (c) the effect of incretin signaling on digestion and nutrient absorption, (d) apoptosis and proliferation of the gut epithelium, (e) if the expression levels and protein levels of key effectors required for fasting or refeeding blocked in mice in which the GLP-1R and GIPR have been deleted. ******The applicant has significant expertise with all of the techniques included in this proposal; therefore trainees will acquire a number of complementary and sophisticated tools/approaches for isolating cells and appropriate use of animals to apply to their future research programs. ******Expected Results and Relevance: We anticipate identifying a critical role for GIPR and GLP-1R signaling in mediating the adaptation of the small intestine to nutrient intake. ************R